Aggressive behavior is a complex social behavior that is influenced by genetic and non-genetic factors. The cost of violence in the US alone is estimated to be $70 billion annually. It is important to understand the mechanisms of aggression to help alleviate this socio-economic burden. In addition, a variety of diseases are characterized by abnormal aggression and little is known about the causes of these behavioral abnormalities, which has hampered the development of successful therapies. We propose to study the transcriptional regulation of aggression in specific neuronal circuits controlling aggression using the model organism Drosophila melanogaster. We will focus on a mechanistic dissection of a conserved transcription factor, Tailless (Tll) (known as Nr2e1 in mammals) with shared binding sites, binding partners and targets in flies and mammals. We recently showed that Drosophila Tll and its conserved co- repressor, Atrophin (Atro), regulate aggression by affecting the activity of a group of neurosecretory neurons in the adult fly brain. We show that Tll controls the release of neuropeptides from these neurosecretory cells and that this is required for increased aggression. These findings further support evidence in the literature that suggest that these neurons have structural, developmental and functional similarities to the hypothalamus, a region critically involved in aggression regulation in mammals. Our studies therefore suggest the existence of an evolutionarily ancient transcriptionally controlled set of neurosecretory cells governing aggressive behavior. In this proposal we will use the large neurobiological and genetic toolkit available in Drosophila to analyze the mechanism of the transcriptional regulation of aggression in flies. We will dissect the neuropeptide-based mechanism that is necessary and sufficient for the regulation of aggression in the PI and we will examine the connection with Tll. To do so, we have developed a new transposon-based tool to study gene-specific expression, allowing functional manipulation of the cells expressing the gene of interest. This tool will be useful for many researchers in the community as it can be applied to many genes in the genome. Finally, we will examine two binding partners of Atro, the co-repressor of Tll that also affects aggression through the neurosecretory cells of the PI and that physically interacts with Tll. One of the binding partners of Atro is encoded by the ortholog of a disease gene mutated in a human syndrome that is characterized by abnormal aggressive behavior. The mechanism of the behavioral abnormalities in these patients is completely unknown as is the case for most of the diseases associated with excessive aggression. Our proposed experiments will help elucidate the role of this gene in aggression. Together the experiments in this proposal will begin to unravel the mechanisms that underlie transcriptional control of aggression in flies. Given the conservation of this molecular pathway, our proposal will open a new direction in the field that will shed light on this complex behavior.